Sulfamyl-anthranilic acids

ABSTRACT

THIS INVENTION RELATES TO NEW 4-SUBSTITUTED 5-SULFAMYLANTHRANILIC ACIDS, AND SALTS AND ESTERS THEREOF, HAVING A PRONOUNCED DIURETIC AND SALURETIC EFFECT; TO METHODS OF PRODUCING THE SAID COMPOUNDS; AND TO PHARMACEUTICAL COMPOSITIONS IN DOSAGE UNIT FORM CONTAINING THE SAID COMPOUNDS AS ACTIVE INGREDIENTS.

United States Patent 3,755,383 SULFAMYL-ANTHRANILIC ACIDS Peter WarnerFeit, Geutofte, and Ole Bent Tvaermose Nielsen, Vanlose, Denmark,assignors to Lovens Kemiske Fabrik Produktionsaktieselskab, Ballerup,Denmark No Drawing. Filed Apr. 23, 1970, Ser. No. 31,413 Claimspriority, application Great Britain, Apr. 29, 1%9, 21,8?0/ 69 Int. Cl.C07c 143/80 US. Cl. 260-3971 7 Claims ABSTRACT OF THE DISCLOSURE Thisinvention relates to new 4-substituted -sulfamylanthranilic acids, andsalts and esters thereof, having a pronounced diuretic and salureticeffect; to methods of producing the said compounds; and topharmaceutical compositions in dosage unit form containing the saidcompounds as active ingredients.

This invention relates to a series of new compounds, to salts and estersof these compounds, and to methods for the production of the compounds.

The new compounds have the General Formula I R1 A N 11 R HN 0 5 C O OHin which A is an R O, RL-S--, R -OS, or R O S-radical, R R R and R eachrepresent an aliphatic radical, a cycloaliphatic radical, or anaromatically, cycloaliphatically or heterocyclically substitutedaliphatic radical provided that when one or both of R and R are hydrogenor an aliphatic radical, A is difierent from an aliphatic R 0 group; Rand R may each also be an aromatic or heterocyclic radical; in additionR may be an acyl radical, or an unsubstituted or substituted carbamylradical. Each of R R and R may also be a hydrogen atom.

In particular, each of R R R and R may represent a straight or branchedchain saturated or unsaturated alkyl radical, e.g. a methyl, ethyl,propyl, isopropyl, butyl, isobutyl, or tert.-butyl radical, one of thedifferent isomeric pentyl, hexyl, and heptyl radicals, an alkenyl oralkynyl radical, e.g. a vinyl, allyl, or propargyl radical, a cycloalkylor cycloalkenyl radical, e.g. a cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, or cyclooctyl radical, one of the diiferentisomeric cyclopentenyl and cyclohexenyl radicals, or an adamantylradical. The aliphatic radicals may further contain hetero atoms, e.g.oxygen, sulphur, or nitrogen, which may interrupt the carbon chain andmay further be substituted, e.g. with lower alkyl radicals. In thearomatically, cycloaliphatically or heterocyclically substitutedaliphatic radicals, the aromatic part of the radical can be a monoorbicyclic aryl radical, e.g. a phenyl or naphthyl radical, thecycloaliphatic part of the radical can be the cycloalkyl or cycloalkenylradicals mentioned above, the heterocyclic part of the radical can be amonoor bicyclic radical containing one or more oxygen, sulphur, andnitrogen atoms as ring members, e.g. 2-, 3-, or 4-pyridyl, 2- or3-furyl, or thienyl, thiazolyl, imidazolyl, benzirnidazolyl, and thecorresponding hydrogenated ring-systems, and the aliphatic part of theradicals can contain 1 to 4 carbon atoms. As illustrative examples ofsuch aromatically and heterocyclically substituted aliphatic radicalscan be mentioned benzyl, 1- and Z-phenylethyl, 1- and 2-naphthyl-methyl, furyl-rnethyl, thienyl-methyl, and the correspondingethyl, propyl, and butyl radicals. When such aromatically orheterocyclically substituted aliphatic radicals are present at thenitrogen atom, and A represents an aliphatic R 0 group, especiallyvaluable products are obtained when R is a C alkyl group. When R and Rrepresent aromatic or heterocyclic radicals, these can be the monoorbicyclic radicals already mentioned above.

All the above mentioned radicals can be substituted in difierentpositions with different groups, such as one or more halogen atoms, e.g.chlorine or bromine atoms, alkyl, halo-alkyl, e.g. trifiuoromethyl,carboxy, carbalkoxy or carbamyl radicals, di-lower alkyl amino radicals,hydroxy groups, which may be etherified or esterified, or etherifiedmercapto groups.

The salts of the compounds of the invention are pharmaceuticallyacceptable salts, e.g. alkali metal salts, alkaline earth metal salts,ammonium salts, or amine salts formed, for instance, from mono-, di-, ortrialkylamines, or mono-, di-, or trialkanolamines or cyclic amines. Theesters of the compounds are preferably derived from lower aliphaticalcohols and benzylalcohols.

The compounds of the invention possesses valuable therapeutic propertiesand have, according to animal experiments performed in connection withthe present invention, a particularly strong eiiect as diuretics andsaluretics, the ratio between the excretion of sodium ions and potassiumions being very favourable. Furthermore, the compounds are notcarboanhydrase inhibitors, and these facts in connection with afavourable therapeutic index make the present compounds particularlyvaluable.

For instance, the diuretic effect has been compared to that of thewell-known diuretic Furosemide, belonging to the group ofchlorosulfamylanthranilic acids.

The diuretic and saluretic activity of4-phenoxy-5-sulfamyl-N-(furyl-2-methyl)-anthranilic acid, in the tablebelow called OT 1190, was primarily determined in animal experiments inwhich the test animals, dogs, after a control period of 2 hours weregiven by intravenous injection a dose of 0.1 mg./kg. of the substance inthe form of its sodium salt which compared to an injection of 4 mg./kg.of Furosemide gave almost the same excretions as will be seen from thetable below. Besides the volume of urine excreted within three hours,the amounts of milli-equivalents of Na+ and Clexcreted were alsodetermined.

Compound M1. or urine Na+ Cl- Controls (average) 2 (ONO 0 Furosemide 4.

Another object of the invention resides in the selection of a dose ofone of the compounds of the invention, or their salts or esters, whichcan be administered so that the desired activity is achieved withoutsimultaneous secondary effects. In such a dosage unit, the compound isconveniently administered as a pharmaceutical composition containingfrom 0.1 mg. to mg. of the active compound. The compounds of Formula I,in which R and R are hydrogen, R is either benzyl, furylmethyl,thienylmethyl, or lower alkyl having from 3 to 6 carbon atoms, A is R 0or R 8, and R is phenyl, are particularly active and are preferablyadministered in amounts from 0.5 mg. to 25 mg. By the term dosage unitis meant a unitary, Le. a single dose capable of being administered to apatient, and which may be readily handled and packed, remaining as aphysically stable unit dose, comprising either the active material assuch or a mixture of it with a pharmaceutical carrier and auxiliaryagents.

In the form of a dosage unit, the compound may be administered one ormore times a day with appropriate .can vary between 0.5 percent and 90percent by weight.

The composition can either be made up in pharmaceutical forms ofpresentation, such as tablets, pills, drages, and suppositories, or thecomposition can be filled in medical containers, such as capsules orampoules, or, as far as mixtures are concerned, filled in bottles ortubes and similar containers.

Pharmaceutical organic or inorganic, solid or liquid carriers suitablefor oral, enteral, and parenteral administration can be used to make upthe compositions. Water, gelatine, lactose, starch, magnesium stearate,talc, vegetable and animal oils and fats, benzyl alcohol, gums,polyalkylene glycol, petroleum jelly, cocoa butter, lanolin, and otherknown carriers for medicaments are all suitable as carriers, whilestabilizing agents, wetting or emulsifying agents, salts for varyingosmotic pressure, and butters for securing an adequate pH-value of thecomposition can be used as auxiliary agents.

Thus for compositions in the form of tablets or the like, or ininjectable compositions, the sodium salt or the potassium salt may beused, as it is sufficiently watersoluble. For injectable compositions,however, salts with certain organic bases may advantageously be employeddue to their high degree of solubilty in water.

The free acid may be administered in capsules, or in tablets, of whichthe latter may be efiervescent-tablets in order to obtain fastabsorption, or they may be sustained-release tablets in order to obtaina prolonged eflect which may be desirable in the treatment ofhypertension. If the composition is to be injected, a sealed ampoule, avial or a similar container may be provided, containing a parenterallyacceptable aqueous or oily injectable solution or dispersion of theactive material.

The compositions may further contain other therapeutically activecomponents suitable in the treatment of hypertension and oedematousconditions, such as a hypotensor, e.g. hydralazin, methyldopa, reserpin,rescinnamine, or protoveratrine, or other Rauwolfiaor Veratrumalkaloids, and/or a tranquilizer, such as2:2-di(carbamoyloxymethyD-pentane (meprobamate), and/or other diureticsand saluretics, such as the well-known benzothiadiazines, e.g.hydroflumethiazidc or bendroflumethiazide. Potassium-sparing compounds,e.g. triamterene or 1-(3,5- diamino-6-chloropyrazinecarboxyl)-quianidineor related compounds, may also be used in the preparation of thecompositions.

For some purposes it may be desirable to add small amounts ofcarboanhydrase inhibitors or aldosterone antagonists, e.g.spironolactone.

The pharmaceutical compositions in dosage unit forms are useful in thetreatment of oedematous conditions, e.g. cardiac, hepatic, renal, lung,or brain oedema, or oedematous conditions during pregnancy, and ofpathological conditions which produce an abnormal retention of theelectrolytes of the body, as Well as in the treatment of hypertensionand congestive heart failure.

The compounds of the invention may be prepared by various methods, forexample according to the following reaction scheme:

1 Hal- Hal A N-R R HNO S COOH YJHNO; C H

wherein the substituents A, R R and R are as defined before, and Halstands for the same or different halogen atoms, preferably chlorine andfluorine.

The conversion of the compounds of Formula II into the compounds of theinvention may be effected in two steps, whereby the two halogen atomsare replaced by the groups -A and respectively. The activating influenceof the sulfamyl and carboxylic acid group on the halogen atoms, and thechoice of a particular pair of halogen atoms will determine which of thetwo halogen atoms will first be replaced whereby two intermediates ofthe Formula 111a and IIIb may be obtained:

R1 A- Hal A- N 13? R HNOgS COOH R HNO S 00 OH (Hm) (IIIb) The startingcompounds of Formula II are known compounds or, if new, they can beprepared by the same methods as the known ones by chlorosulfonation of a2,4-dihalo-benzoic acid, in which the two halogen atoms can be differentor the same, advantageously by using an excess of chlorosulfonic acid.The resulting sulfochloride is then reacted with an amine, R -NH Thisamination is preferably performed below or at room temperature and withor without solvents, depending on the amine used in the reaction. Theamine is preferably used in an amount of at least two equivalents, inorder to bind the hydrogen halide formed by the process. Other basicagents for binding the hydrogen halide can be used as well.

In the starting compounds so obtained, the two halogen atoms may be thesame, in which case the halogen in the 2-position, i.e. in theortho-position to the carboxylic group, will be more reactive than thatin the 4-position, whereby a reaction with an amine of the formularesults in the well-known compounds of the General Formula IIIb, thereaction conditions in this case being known from the literature.

When the halogen atoms are different, the preferred intermediates arethose in which the reactivity of the halogen in the 4-position is morepronounced than that in the 2-position. Particularly useful are thecompounds of Formula II, in which the halogen atom in the 2-position ischlorine and in the 4-position is fluorine. The reaction of a compoundof this type with a compound of the formula A-H, A being OR SR orO S--Rresults in the compounds of the General Formula 1118.. The reaction canbe performed by heating the two components, if convenient, in thepresence of an organic or inorganic base and, if desired, in thepresence of water or a suitable organic solvent, or mixtures thereof.The isolation of thereaction products can be performed by well-knownstandard procedures.

The reaction between the Compound 111a and an amine HNR R is efiected byheating the components, if necessary in the presence of an inert organicsolvent, using preferably an excess of two or more equivalents of theamine. The temperature depends on the amine used in the process, andwill in most cases preferably be about the boiling point of the amine orthe solvent used.

The reaction between the Compound IIIb and the Compounds A-I-I can beperformed under reaction conditions similar to those described for thepreparation of the Compound HIa.

In the case where R and R in Formula 11th are both hydrogen, theintermediate IIIb can be obtained in known manner from the well-known2-acetamino-4-halogenotoluene, which by chlorosulfonation followed by anamination can be transformed into the analogous2-acetamino-4-halogeno-5-R -sulfamyl-toluene, which can then be oxidizedto the corresponding anthranilic acid derivative by treatment withpotassium permanganate. By an acidic or alkaline hydrolysis. lI Ib (R=R=H) can be obtained. When Hal stands for chlorine, the resultingcompounds are known, and in the same way the corresponding fluoroderivatives can be obtained from the known 4-fluoro-2-acetaminotoluene.Particularly when Hal stands for fluorine in Formula IIIb, both the freeand the acylated anthranilic acid derivatives react under mildconditions with compounds AH to form the compounds of the invention inwhich R =R =H. These compounds can be alkylated to other compounds ofFormula I using standard procedures, and some of the latter can besubjected to a dealkylation resulting in compounds of the invention inwhich R =R =H.

In the case where A stands for a radical of the sulfinyl or sulfonylseries, the compounds of the invention are preferably prepared from thecorresponding mercapto derivatives by oxidation with, for instance,hydrogen peroxide. Depending upon the amount of hydrogen peroxide andthe reaction conditions, the oxidation results in the sul-finyl or thesulfonyl derivatives.

The isolation of the reaction products can be carried out in knownmanner. If the products are obtained as salts or esters, they can, ifdesired, be converted into the free acids in known manner. The compoundsof Formula I in which R is an acyl or a carbamyl group can be obtainedpreferably from the corresponding compounds in which R is hydrogen byreacting them under alkaline conditions with an acid or a reactivederivative thereof, or with an isocyanate, respectively.

Some of the starting materials are new and are prepared in the followingmanner:

2,4-DIFLUORO-5-SULFAMYL-BENZOIC ACID 2,4-difiuorfobenzoic acid (17.5 g.)is added in portions to chlorosulfonic acid (70 ml.) at room temperaturewhile stirring. The mixture is then stirred at 155160 C. for 2 hours,cooled and carefully added to ice (about 300 g.). The precipitated5-chlorosulfonyl-2,4-difiuorobenzoic acid is collected by filtration andwashed with cold water. The crude sulfochloride is added in portions toconcentrated ammonium hydroxide (160 ml.) while stirring at -l2 C. Afterthe addition has been completed, the stirring is continued at roomtemperature for a further hours. The solution is carefully acidifiedwith concentrated hydrochloric acid, and the resulting precipitate iscollected by filtration and washed with water. After drying,2,4-difluoro-S-sulfamyl-benzoic acid is obtained With a melting point of203204 C. Recrystallization from aqueous ethanol raises the meltingpoint to 203.5- 204.5 C.

ETHYL Z-CHLORO-4-FLUORO-5-SULFAMYL- BENZOATE A solution of2-chloro-4-fluoro-5-sulfamyl-benzoic acid g.) in ethanol (500 ml.) issaturated with hydrogen chloride and left overnight. The solution isevaporated in vacuo, and the residue is triturated with saturated sodiumhydrogen carbonate solution (about 250 ml). The undissolved material iscollected by filtration and washed with water. After drying, ethyl2-chloro-4-fiuoro5-sulfamyl-benzoate is obtained with a melting point of135- 137 C. After recrystallization from 50 percent ethanol, the meltingpoint is unchanged.

METHYL 2-CHLORO-4-FLUORO-S-SULFAMYL- BENZOATE By replacing ethanol bymethanol in the above procedure, methyl2-chloro-4-fiuoro-S-sulfamyl-benzoate is obtained with a melting pointof 173-l75 C 6 ETHYL 2,4-DIFLUORO-S-SULFAMYL- 'BENZOATE By replacing the2-chloro-4-fiuoro-5-sulfamylbenzoic acid of the above procedure by2,4-difiuoro-5-sulfamylbenzoic acid, ethyl2,4-difiuoro-S-sulfamyl-benzoate is obtained with a melting point ofl33135 C.

4-FLUORO-S-SULFAMYLANTHRANILIC ACID (a)3-acetamino-4-fiuoro-5-sulfamyl-toluene A mixture ofZ-acetamino-4-fluoro-toluene (20 g.), so dium chloride (8.0 g.), andchlorosulfonic acid (50 ml.) is heated on a steam bath for 2 hours. Themixture is then poured onto ice (about 300 g.), and the precipitatedsulfochloride is filtered off and washed with Water. The partially driedsulfochloride is added in small portions to anhydrous ammonia (aboutml.), While stirring, and the mixture is left overnight. Cold Water (100ml.) is added, and the precipitate is filtered off and washed withWater. After drying, 2-acetamino-4-fluoro-5-sulfamyltoluene is obtainedwith a melting point of 206208 C. Recrystallization from ethanol raisesthe melting point to 2l1-212 C.

(b) 4-fluoro-5-sulfamyl-N-acetyl-anthranilic acid To a suspension of2-acetamino-4-fluoro-5-sulfamyltoluene (12.0 g.) in 10 percent aqueousmagnesium sulfate solution (200 ml.), potassium permanganate (36.0 g.)is added in portions within 30 minutes at 90-95 C., while stirringvigorously. The mixture is then stirred at this temperature for afurther 2 hours. Excess potassium permanganate is destroyed by additionof aqueous sodium hydrogen sulfite. The precipitated manganese dioxideis filtered olf and washed with hot water (50 ml.). The combinedfiltrates are acidified with concentrated hydrochloric acid (20 ml.),and the resulting precipitate is filtered off and washed with water.After drying, 4-fluoro- 5-sulfamyl-N-acetyl anthranilic acid is obtainedwith a melting point of 247-249 C. (dec.). Recrystallization fromethanol raises the melting point to 257-258 C. (dec.).

(c) 4-fluoro-5-sulfamyl-anthranilic acid A solution of4-fluoro-5-sulfamyl-N-acetyl-anthranilic acid (0.8 g.) in 4 N sodiumhydroxide (5 ml.) is heated on a steam bath for 2 hours. After cooling,the solution is acidified with' acetic acid (2.5 ml.), and the resultingprecipitate is filtered off and washed with water, After drying,4-fluoro-5-sulfamyl-anthranilic acid with a melting point of 261-262" C.is obtained.

The invention will now be illustrated by the following non-limitingexamples.

EXAMPLE 1 4-phenoxy-5-sulfamyl-N-benzyl-anthranilic acid (a)2-chloro-4-phenoxy-S-sulfamyl-benzoic acid.A mixture of2-chloro-4-fluoro-5-sulfamyl-benzoic acid (12 g.), phenol (50 g.), andpotassium hydroxide (12.5 g.) is heated to 1'50160 C. for 3 hours Whilestirring. The mixture is diluted with water, extracted twice withdiethyl ether and carefully acidified with concentrated hydrochloricacid (15 ml.). The precipitated oil is crystallized from water andfiltered off. After drying, 2-chloro-4- phenoxy-S-sulfamyl-benzoic acidis obtained with a melting point of 198 C. (dec.). Recrystallizationfrom aqueous ethanol raises the melting point to 206.5- 207.5 C.

(b) 4-phenoxy-5-sulfamyl-N-benzyl-anthranilic acid.- A mixture of2-chloro-4-phenoxy-5-sulfamyl-benzoic acid (10 g.) and benzylamine (40ml.) is heated to l30135 C. for 4 hours. The mixture is poured into cold4 N acetic acid (200 ml.), and the resulting precipitate is filtered offand washed with Water, c-old ethanol, and diethyl ether. After drying,4-phenoxy-5-sulfamyl-N-benzylanthranilic acid is obtained with a meltingpoint of 239- 240 C. (dec.). Recrystallization from ethanol raises themelting point to 241.5-243" C. (dec.).

EXAMPLES 2-11 By following the procedure described in Example lb, butreplacing the benzylamine by the amines of the following Table II, thecorresponding 4-phenoxy-5-sulfamyl-N-substituted-anthranilic acids areobtained:

6 2 chlorob enzylamine N-(2-chlorobenz yl) 258.5-259 (dec.). 7 1-methoxybenzyl- N-(4-methoxybenzyl) 195195.5 (dec.)

amine. 8- 3-methylbenzylamine- N-(3-methylbsnzyl)... 237-238 (dec.).

(semihydrato).

11 N-methylbenzyl- N-benzyl-N-methyl. 202202.5 (dec.).

amine.

EXAMPLE 12 4-phenoxy-S-sulfamyl-N-allyl-anthranilic acid A mixture of2-chloro-4-phenoxy-5-sulfamyl-benzoic acid (5.0 g.) and allylamine (50ml.) is refluxed for 90 hours and thereafter evaporated in vacuo. Theresidue is triturated with a mixture of 4 N acetic acid (35 ml.) andconcentrated hydrochloric acid ml.). The resulting crystalline materialis collected by filtration and washed with water. The material isextracted with hot saturatedsodium hydrogen carbonate solution (25 ml.)and filtered hot in the presence of decolourizing carbon. The clearfiltrate is carefully acidified with concentrated hydrochloric acid (4ml.). The resulting precipitate is collected by filtration and washedwith water. After drying and crystallizing twice from ethanol,4-phenoxy- 5-sulfamyl-N-allyl-anthranilic acid is obtained with amelting point of 229-230 C. (dec.).

EXAMPLE 13 4-phenoxy-5-sulfamyl-N-n-butyl-authranilic acid A mixture of2-chloro-4-phenoxy-S-sulfamyl benzoic acid (2 g.), n-butylarnine (15mL), and water (5 ml.) is refluxed for about 72 hours. The mixture isevaporated in vacuo, and the residue is crystallized With 4 N aceticacid m1.), filtered OE, andwashed with water. After drying andrecrystallizing twice from aqueous ethanol,4-phenoxy-5-sulfamylN-n-butyl-anthranilic acid is obtained with amelting point of 217-219 C. (dec.).

EXAMPLES 14-15 55 By following the procedure described in Example 13,but replacing the n-butylamine by isobutylamine and npentylamine andextending the reaction time to 96 hours and 110 hours, respectively, the4-phenoxy-S-sulfamyl-N- isobutyl-anthranilic acid with a melting pointof 220- 60 221 C. (dec.) and 4-phenoxy-5-sulfamyl-N-n-pentylanthranilicacid with a melting point of 227-228 C. (dec.) are obtained.

EXAMPLE l6 acetic acid (5 ml.). The resulting precipitate is washed withwater. After drying and recrystallization, 4-phenoxy-5-sulfamyl-N-[furyl-(2)-methyl]-anthranilic acid is obtained with amelting point of 229230 C. (dec.).

EXAMPLE 17 4-phenoxy-5-sulfamyl-N- [thienyl- (2 -methyl] anthranilicacid By following the procedure of Example 16, but replacing thefurfurylamine by Z-thienylarnine, 4-phenoxy-S-suIfamyLS-[thienyl-(ID-methyl]-anthranilic acid with a melting pointof 222 C. (dec.) is obtained.

EXAMPLE l8 4-phenoxy-5-sulfamyl-N-(a-naphthylrnenthyD- anthranilic acidA solution of 4-phenoxy-5-sulfamyl-anthranilic acid (1.54 g.) anda-chloromethylnaphthalene (2.0 g.) in ethanol (25 ml.) is refluxed for65 hours, and thereafter evaporated in vacuo. The oily residue istriturated with Water which is decanted and replaced by 75 percentethanol (15 ml.). On standing for 2 days at 5 C., the oil crystallizes.The crystalline material is collected by filtration and washed with cold50 percent ethanol; it is dissolved in 2 N sodium hydroxide (15 ml.) andheated on a steam bath for 1 hour. The solution is filtered hot in thepresence of decolourizing carbon and is then acidified with concentratedhydrochloric acid (4 ml.). The resulting precipitate is collected byfiltration and washed with water. After drying and recrystallizing froma mixture of ethanol and methyl-cellosolve, 4-phenoxy-5- sulfamyl N (anaphthylmethyl) anthranilic acid with a melting point of 232-233 C.(dec.) is obtained.

EXAMPLE l9 4-phenoxy-5-sulfamyl-N,N-di-n-butylanthranilic acid Asolution of Z-chloro 4 phenoxy 5 sulfamylbenzoic acid (2.0 g.) anddi-n-butylamine (8.0 ml.) in methyl-Cellosolve (10 ml.) is stirred at C.for 40 hours, and is then evaporated in vacuo. The residue is trituratedwith 4 N acetic acid (10 ml.), and the resulting crystalline material iscollected by filtration and washed with Water. The product is extractedwith hot saturated sodium hydrogen carbonate solution (30 ml.) andfiltered hot in the presence of decolourizing carbon. The filtrate isacidified with acetic acid (10 ml.). The resulting precipitate iscollected by filtration and washed with water. After drying andcrystallizing twice from 50 percent ethanol, 4 phenoxy 5 sulfamyl N,N din butylanthranilic acid with a melting point of 172-173 C. is obtained.

EXAMPLE 20 4-phenoxy-5-sulfamyl-N,N-dibenzyl-anthranilic acid (a)4-fiuoro 5 sulfamyl N,N dibenzyl-anthranilic acid.A mixture is2,4-difluoro 5 sulfamyl-benzoic acid (3.0 g.), dibenzylamine (10 ml.),and water (10 ml.) is heated on a steam bath for 2.5 hours. The mixtureis poured into 4 N acetic acid (40 ml.) and left standing overnight. Theprecipitated semi-solid material is triturated with ethanol (25 ml.).The resulting crystalline material is collected by filtration and washedwith ethanol and with diethyl ether. After drying, 4-fiuoro- S-sulfamylN,N dibenzyl anthranilic acid is obtained with a melting point of 215 C.(dec.). After recrystallization from ethanol, the melting point isunchanged.

(b) 4-phenoxy 5 sulfarnyl-N,N-dibenzyl-anthranilic acid.--A mixture of4-fluoro 5 sulfarnyl-N,N-dibenzylanthranilic acid (1.5 g.), phenol (10g.), and potassium hydroxide is stirred at C. for 5 hours. The mixtureis cooled, diluted with water (25 ml.), and acidified to pH 5 withconcentrated hydrochloric acid. The precipitated oil is washed withWater and triturated with ethanol (5 ml.). The resulting crystallinematerial is collected by filtration and Washed With water. After dryingand recrystallizing from ethanol, 4-phenoxy sulfamyl-N,N-dibenzyl-anthranilic acid is obtained as a semi-hydrate with a meltingpoint of 168-169 C. (dec.).

EXAMPLE 21 Ethyl 4- (4-chlorophenoxy -5-sulfamyl-N- benzyl-anthranilate(a) Ethyl 2-chloro 4 (4 chlorophenoxy) 5- sulfamyl-benzoate.-A solutionof ethyl 2-chloro-4-fluoro- 5-sulfamyl-benzoate (2.85 g.),4-chlorophenol (1.5 g.), and sodium (0.25 g.) in ethanol (25 ml.) isrefluxed for 20 hours. The mixture is evaporated in vacuo, and theresidue is triturated with water. The resulting crystalline material iswashed with water and with cold 50 percent ethanol. After drying andrecrystallizing from 50 percent ethanol, ethyl 2-chloro 4 (4'chlorophenoxy) 5- sulfamyl-benzoate is obtained with a melting point of142-143 C.

(b) Ethyl 4 (4' chlorophenoxy) 5 sulfamyl-N- benZyl-anthranilate.Amixture of ethyl 2-chloro-4-(4- chlorophenoxy) 5 sulfamyl benzoate (2.0g.) and benzylamine (6.0 ml.) is heated on a steam bath for 2 hours. Themixture is then poured into cold 4 N acetic acid (50 ml.), and theresulting precipitate is washed with water. After drying andrecrystallizing from ethanol, ethyl 4 (4' chlorophenoxy) 5 sulfamyl Nbenzylanthranilate is obtained with a melting point of 202- 203 C.

EXAMPLE 22 4-(4'-chlorophenoxy)-5-sulfamyl-N-benzylanthranilic acid Amixture of ethyl 4 (4' chlorophenoxy) 5 sulfamyl N benzyl anthranilate(2.0 g.) and 2 N sodium hydroxide is heated on a steam bath for 1 hour.The solution is cooled and acidified with concentrated hydrochloric acid(4 ml.). The resulting precipitate is collected by filtration, washedwith water and with cold ethanol. After drying and recrystallizing froma mixture of ethanol and methyl-Cellosolve, 4 (4'chlorophenoxy)-5-sulfamyl-N-benzyl-anthranilic acid is obtained with amelting point of 262-263" C. (dec.).

EXAMPLES 23-24 By following the procedure of Example 21, step a, andreplacing the 4-chlorophenol by 2-fluorophenol (1.25 g.) and fl-naphthol(1.6 g.), respectively, the ethyl 2-chloro- 4 (2' fluorophenoxy) 5sulfamyl benzoate and the ethyl 2-chloro 4 (B-naphthoxy) 5sulfamyl-benzoate with a melting point of 139-140 C. and 172-173 C.,respectively, are obtained which by following the procedure of step bare converted into ethyl 4-(2' fluorophenoxy) 5 sulfamyl Nbenzyl-anthranilate with a melting point of 132-134 C. and 189-190 C.,respectively.

EXAMPLES 25-26 By replacing, in Example 22, the ethyl4-(4'-chlorophenoxy) 5 sulfamyl N benzyl anthranilate by the ethylesters of Examples 23 and 24, the 4-(2'-fiuorophenoxy) 5 sulfamyl Nbenzyl-anthranilic acid and the 4-(fl-naphthoxy) 5sulfamyl-N-benZyl-anthranilic acid, respectively, are obtained with themelting points of 248-2485 C. and 255-257" C.

EXAMPLE 27 4-(3'-pyridyloxy) -S-suIfamyI-N-benzyl-anthranilic acid (a) 2chloro 4 (3' pyridyloxy) 5 sulfamyl benzoic acid.-By replacing the4-chlorophenol of Example 21, step a, by S-hydroxypyridine (1.2 g.) andsaponifying the intermediate ethyl 2 chloro 4 (3'- pyridyloxy) 5sulfamylbenzoate, 2 chloro 4 (3- pyridyloxy) 5 sulfamyl benzoic acidhydrochloride is obtained with a melting point of 269-270 C. (dec.).

b 4-( 3-pyridyloxy) -5-sulfamyl-N-benzyl-anthranilic acid.By replacing,in Example 21, step b, the ethyl 2- chloro-4-(4-chlorophenoxy) 5sulfamyl-benzoate by 2-chloro-4-(3'-pyridyloxy)-5-sulfamyl-benzoic acid,4-(3- pyridyloxy)-5-sulfamyl-N-benzyl-anthranilic acid hydrate isobtained with a melting point of 245-246 C. (dec.).

EXAMPLES 28-30 Following the procedure of Example 1, steps a and b, andreplacing the phenol by 3-methoxyphenol, 3-methylphenol, and3-trifluoromethylphenol, respectively, the corresponding4-(3'-methoxyphenoxy)-, 4-(3'-methoxyphenoxy)-, and4-(3'-trifluoromethylphenoxy)-5-sulfamyl-N- benzylanthranilic acid areobtained with melting points of 214.5-216 C., 229.5-231 C., and 226-227C. (dec.).

EXAMPLE 31 4-phenoxy-5-sulfamyl-anthranilic acid A suspension of4-phenoxy-5-sulfamyl-N-benzyl-an thranilic acid (4 g.) in percentethanol ml.) and concentrated hydrochloric acid (0.2 ml.) ishydrogenated at 1.1 atmospheres in the presence of palladium (10percent) on charcoal (0.5 g.). The theoretical amount of hydrogen isabsorbed in about 40 minutes. The catalyst is removed by filtration, andthe filtrate is evaporated in vacuo. The resulting crystalline materialis triturated with 4 N acetic acid (10 ml.), filtered off, and washedwith Water. After drying, 4 phenoxy 5 sulfamylanthranilic acid isobtained With a melting point of 233- 234 C. The melting point isunchanged after recrystallization from aqueous ethanol.

EXAMPLE 32 4-phenoxy-5-sulfamyl-N-benzyl-anthranilic acid A mixture of4-phenoxy-S-sulfamyl-anthranilic acid (0.31 g.), benzaldehyde (0.15 g.),and acetic acid (4 ml.) is hydrogenated at 1.1 atmospheres in thepresence of PtO (0.01 g.). The theoretical amount of hydrogen isabsorbed in about 4 hours. Water (4 ml.) is added, and the mixture isleft overnight. The resulting precipitate is filtered oil? and Washedwith Water. The acid is dissolved in 1 N sodium hydroxide (5 ml.), andthe catalyst is removed by filtration. The filtrate is acidified withacetic acid (1 ml.), and the resulting precipitate is filtered andwashed with water. After drying and recrystallizing from ethanol,4-phenoxy-5-sulfamyl-N-benzyl-anthranilic acid is obtained with amelting point of 241-242.5 C. (dec.). The material is identical (IRanalysis) with the material prepared as in Example 1b.

EXAMPLE 33 4-phenoxy-5-sulfamyl-N-benzyl-anthranilic acid A solution of4 phenoxy-5-sulfamyl-anthranilic acid (5.0 g.) and benzyl bromide (5.0ml.) in methyl-Cellosolve (50 ml.) is heated on a steam bath for 18hours and is thereafter evaporated in vacuo. The semi-solid residue iswashed with water and triturated with ethanol (25 ml.). The resultingcrystalline material is collected by filtration and Washed with water.After drying and recrystallizing from ethanol, 4 phenoxy 5 sulfamyl-N-benzyl-anthranilic acid is obtained with a melting point of 240 242 C.(dec.). The material is identical (IR analysis) with the material asprepared in Example lb.

EXAMPLE 34 4- (2-methoxy-ethoxy) -5-sulfamyl-N-benzylanthranilic acid(a) 2 chloro 4 (2' methoxy-ethoxy)-5-sulfamylbenzoic acid.A mixture of2-ch10ro-4-fluoro-S-sulfamylbenzoic acid (2.5 g.), sodium (0.5 g.), andethylene glycol monomethyl ether (methyl-Cellosolve) (10 ml.) is

refluxed for 20 hours. The mixture is evaporated in vacuo, and theresidue is treated with 1 N hydrochloric acid (25 ml.). The precipitatedoil is crystallized from aqueous acetonitrile, filtered off, and washedwith Water. After drying and recrystallizing from acetonitrile,Z-chloro- 4-(2'-methoxy-ethoxy)-5-sulfamyl-benzoic acid is obtained witha melting point of 216-218 C.

(b) 4 (2 methoxy ethoxy)--sulfamyl-N-benzylanthranilic acid.--A solutionof 2-ch1oro-4-(2-methoxyethoxy)-S-sulfamylbenzoic acid (0.8 g.) andbenzylamine (4.0 ml.) in methyl-Cellosolve (8 ml.) is refluxed for 18hours. The solution is evaporated in vacuo, and the residue is treatedwith 2 N hydrochloric acid (20 ml.). The resulting precipitate isfiltered ofi and washed with water. After drying and recrystallizingfrom ethanol, 4- (2'-methoxy-ethoxy) 5 sulfamyl-N-benzyl-anthranilicacid is obtained with a melting point of 2l3-2l4 C. (dec.).

EXAMPLE 35 4-n-butyloxy-5-sulfarnyl-N-benzyl-anthranilic acid (a)4-n-butyloxy 2 chloro-S-sulfamyl-benzoic acid. A mixture of2-chloro-4-fluoro-5-sulfamylbeuzoic acid (2.55 g.) and sodium (0.7 g.)dissolved in n-butanol (20 ml.) is stirred at 130 C. for 20 hours. Themixture is cooled and diluted with petroleum ether (boiling point 50-70C., 20 ml.). The resulting precipitate is collected by filtration andWashed with petroleum ether. The crude sodium4-n-butyloxy-2-chloro-S-suIfamyl-benzoate is dissolved in water (20ml.), and the solution is acidified with concentrated hydrochloric acid(3 ml.). The resulting precipitate is collected by filtration and washedwith water. After drying and recrystallizing from 50 percent ethanol,4-n-butyloxy-2-chloro-5-sulfamyl-benzoic acid hydrate is obtained with amelting point of 175176 C.

(b) 4-n-butoyloxy 5 sulfamyl-N-benzyl-anthranilic acid.-By replacing, inExample lb, the 2-chloro-4-phenoxy-5-sulfamyl-benzoic acid by4-n-butyloxy-2-chloro-5- sulfamyl-benzoic acid hydrate,4-n-butyloxy-5-sulfamyl- N-benzyl-anthranilic acid is obtained with amelting point of 242-243 C. (dec.).

EXAMPLE 36 4-n-butyloxy-5-sulfamyl-N-[furyl-(2)-methyl]- anthranilicacid By replacing, in Example 16, the 2-chloro-4-phenoxy- 5sulfamyl-benzoic acid by 2 chloro-4-n-butyloxy-5- sulfamyl-benzoic acid,4-n-butyloxy-5-sulfamyl-N-[furyl- (2)-methyl]-anthranilic acid isobtained with a melting point of 222-2225 C. (dec.).

EXAMPLE 37 4-phenylthio-5-sulfamyl-N-n-butyl-anthranilic acid Byreplacing, in Example 13, the 2-chloro-4-phenoxy- S-sulfamyl-benzoicacid by 2-chloro-4-phenylthio-S-sulfamyl-benzoic acid, 4phenylthio-S-sulfamyl-N-n-butylanthranilic acid is obtained with amelting point of 246- 247 C. (dec.).

EXAMPLE 38 4-phenylthio-5-sulfamyl-N-benzyl-anthranilic acid (a) 2chloro 4 phenylthio 5 sulfamly benzoic acid.A solution of2-chloro-4-fiuoro-S-sulfamyl-benzoic acid (12.7 g.), thiophenol (8 g.)and sodium hydrogen carbonate (25 g.) in water (100 ml.) is heated on asteam bath for 5 hours. After cooling, the mixture is carefullyacidified with concentrated hydrochloric acid (30 ml.). The resultingprecipitate is filtered oif and washed with water. After dirying andrecrystallizing from aqueous acetonitrile, 2 chloro4-phenylthio-5-sulfamly-benzoic acid with a melting point of 257260 C.(dec.) is obtained.

From the mother liquors, a further crop with a melting point of 254256C. (dec.) is obtained. Recrystalliza- 12 tion from aqueous ethanolraises the melting point to 258.5-260 C. (dec.).

(b) 4 phenylthio 5 sulfamly-N-benzyl-anthranilic acid-A mixture of2-chloro-4-phenylthio-5-sulfamylbenzoic acid (6 g.) and benzylamine (20ml.) is heated to 140 C. for 4 hours. The mixture is poured into cold 4N acetic acid ml.), and the resulting precipitate is filtered olf andwashed with water. After drying and recrystallizing from ethanol, crude4-phenylthio-5-sulfamyl- N-benzyl-anthranilic acid is obtained with amelting point of 245-247 C. (dec.).

EXAMPLE 39 4-pheuylthio-5-sulfamyl-N-benzyl-anthranilic acid4-ph.enylthio-5-sulfamyl-N- [furyl-(2)-methyl]- anthranilic acid Asolution of 4 chloro 5-sulfamyl-N-[furyl-(2)- methylJ-anthranilic acid(3.3 g.), thiophenol (6 ml.) and sodium hydrogen carbonate (10 g.) inwater (20 ml.) and methyl-cellosolve (20 ml.) is refluxed for 48 hourswhile stirring. The mixture is diluted with water (100 ml.) and, aftercooling, acidified to pH 4 with acetic acid. The resulting precipitateis filtered olf and washed with water, ethanol, and diethyl ether. Afterdrying and recrystallizing from methyl-cellosolve, crude4-phenylthio-S-sulfamyl-N- [fury-(2)-methyl]-anthranilic acid isobtained with a melting point of 245-246 C. (dec.).

EXAMPLE 41 4-phenylthio- 5 -sulfamyl-N- [pyridyl- 3 -methyl] anthranilicacid A solution of 2-chloro-4-phenylthio-S-SuIfamyI-benzoic acid (2 g.)and 3-picolylamine (8 ml.) in methyl Cellosolve (8 ml.) is refluxed for18 hours. The mixture is evaporated in vacuo, and the residue iscrystallized from 4 N acetic acid (25 ml.). The resulting material isfiltered olf and washed with water. After drying and recrystallizingfrom methyl-cellosolve, 4-phenylthio-5-sulfamyl-N-[pyridyl-(3)-methyl]-anthranilic acid is obtained with amelting point of 260-261.5 C. (dec.).

EXAMPLE 42 4-phenylthio-S-sulfamyl-N,N-di-n-butyl-anthranilic acid Asolution of 2-chloro-4-phenylthio-5-sulfamly-benzoic acid (2.0 g.) anddi-n-butylamine (8.0 ml.) in methylcellosolve (10 m1.) is refluxed for40 hours. The solution is evaporated in vacuo, and residue is treatedwith 4 N acetic acid (10 ml.). The resulting crystalline material isfiltered OE and washed with water. After drying and recrystallizingtwice from ethanol, 4-phenylthio-5-sulfamly-N,N-di-n-butyl-anthranilicacid is obtained with a. melting point of 205-206" C. (dec.).

EXAMPLE 43 4-phenylthio-S-sulfamyl-N,N-dibenzyl-anthranilic acid Amixture of 4-fluoro-5-sulfamyl-N,N-diebnzyl-anthranilic acid (1.25 g.),thiophenol (1.0 ml.), sodium hydrogen carbonate (3.0 g.), and water (15ml.) is heated on a steam bath for 24 hours. The resulting solution isfiltered hot in the presence of decolourizing carbon, and the clearfiltrate is acidified with concentrated hydrochloric acid (4 ml.). Theresulting precipitat sei collected by filtration and washed with water.After drying, 4-phenylthio-5sulfamly-N,N-dibenzyl-anthranilic acidhydrate with a melting point of about 185 C. (dec.). (after loss ofwater of crystallization at 115 C.) is obtainted. Recrystallization fromethanol raises the melting point to 189l90 C. (dec.) (water lost at 155C.).

EXAMPLE 44 4-(4-acetaminophenylthio)-5-sulfamylN-benzy1- anthranilicacid (a) Ethyl 4 (4 acetaminophenylthio)-2-chloro-5-sulfamyl-benzoate.By replacing, in Example 21a, the 4- chlorophenol by4-acetaminothiophenol (1.9 g.), 4-(4'- acetaminophenylthio) 2 chlorosulfamly-benzoate is obtained with a melting point of 234-235 C.

(b) Ethyl 4 (4 acetaminophenylthio)-S-snlfamyl-N-benzyl-anthraniliate.By replacing, in Example 21b, the ethyl 2 chloro4-(4'-chlorophenoxy)-S-sulfamlybenzoate by ethyl4-(4-acetaminophenylthio)-2-chloro-5- slulfamyl-benzoate (2.0 g.), ethyl4-(4'-acetam1nophenylthio) 5 sulfamyl-anthraniliate is obtained with amelting point of 237-238 C.

(c) 4 (4 acetaminophenylthio) 5 sulfamyl-N- benzyl-anthranilic acid.Asolution of ethyl 4-(4'-acetaminophenylthio) 5sulfamyl-N-benzyl-anthraniliate (1.5 g.) in a mixture of 1 N sodiumhydroxide (7.5 ml.) and water (12 ml.) is stirred at room temperaturefor 20 hours. The solution is acidified with acetic acid (3.0 ml.), andthe resulting precipitate is collected by filtration and washed withwater. After drying, 4-(4-acetaminophenylthio) 5sulfamyl-N-benzylanthranilic acid with a melting point of 250 C. (dec.)is obtained. Recrystallization from methyl-Cellosolve raises the meltingpoint to 266-267" C. (dec.).

EXAMPLE 45 4- (3 '-methylphenylthio -5-sulfamyl-N-b enzylanthranilicacid (a) 2-chloro-4-(3-methylphenylthio)-5-sulfamyl-benzoic acid.Byreplacing, in Example 38a, the thiophenol by 3-methylthiophenol,2-chloro-4-(3'-methylphenylthio)- 5-sulfamyl-benzoic acid with a meltingpoint of 23023l C. is obtained.

(b) 4 (3-methylphenylthio)-5-sulfamyl-N-benzyl-anthranilic acid.Byreplacing, in Example 38b, the 2- chloro-4-phenylthio-5-sulfamyl-benzoicacid by 2-chloro- 4-(3-methylphenylthio)-5-sulfamyl-N benzyl-anthranilicacid with a melting point of 248-250 C. (dec.) is obtained.

EXAMPLE 46 4-n-butylthio-5-sulfamyl-N-benzyl-anthranilic acid (a) Ethyl4-n-butylthio-2-chloro-5-sulfamyl-benzoate-By replacing in Example 21a,the 4-chlor0phenol by n-butylmercaptane (1.25 ml.) and decreasing thereaction time to two hours, ethyl4-n-butylthio-2-chloro-S-sulfamylbenzoate is obtained with a meltingpoint of 99-101 C.

(b) Ethyl 4-n-butylthio-5-sulfamyl-N-benzyl-anthranilate-By replacing,in Example 21b, the ethyl 2-chloro-4-(4'-chlorophenoxy)-5-sulfarnyl-benzoate by ethyl4-n-butylthio-2-chloro-S-sulfamyl-benzoate (2.0 g.), ethyl4-nbutylthio-S\sulfamyl-N-anthranilate is obtained with a melting pointof ISO-182 C.

(c) 4 n butylthio 5 sulfamyl-N-benzyl-anthranilic acid.-By replacing, inExample 22, the ethyl 4-(4'-chlo-'rophenoxy)-5-sulfamyl-N-benzyl-anthranilate by ethyl4-nbutylthio-S-sulfamyl-N-benzyl-anthranilate (2.0 g.),4-nbutylthio-S-sulfamyl-N-benzyl-anthranilic acid is obtained with amelting point of 236237 C EXAMPLE 47 4-(2.'-phenylethylthio-5-sulfamyl-N-benzylanthranilic acid (a)2-chloro-4-(2-phenylethylthio)-5-sulfamyl-benzoic acid.By replacing, inExample 38a, the thiophenol by B- phenylethylmercaptane and extendingthe reaction time to 20 hours,2-chloro-4-(2-phenylethylthio)-5-sulfamyl-benzoic acid is obtained witha melting point of 201202 C.

(b) 4- 2'-phenylethylthio) -5-sulfamyl-N-benzyl-anthranilic acid-Byreplacing, in Example 38b, the 2-chloro-4- phenylthio-5-sulfamyl-benzoicacid by 2-chloro-4-(2- phenylethylthio)-5-sulfamyl-benzoic acid,4-(2-phenylethylthio)-5-sulfamyl-benzoic acid, 4 (2'phenylethylthio)-5-sulfamyl-N-benzyl-anthranilic acid is obtained with amelting point of 234246 C. (dec.).

EXAMPLE 48 4-phenylthio-5-sulfamyl-anthranilic acid (a) 4 phenylthio 5sulfamyl N acetyl-anthranilic acid-A solution of4-fluoro-5-sulfamyl-N-acetyl anthranilic acid (2.0 g.), thiophenol (5.0ml.), and sodium hydrogen carbonate (8.0 g.) in water (25 ml.) is heatedon a steam bath for 6 hours. After cooling, the mixture is extractedtwice with diethyl ether, and the aqueous solution is carefullyacidified With concentrated hydrochloric acid. The resulting precipitateis filtered off and Washed with water. After drying and recrystallizingfrom ethanol, 4- phenylthio-S-sulfamyl-N-acetyl anthranilic acid isobtained with a melting point of 222 C. (dec.).

(b) 4-phenylthio-5-sulfamyl-anthranilic acid.A mixture of4-phenylthio-5-sulfamyl-N-acetyl-anthranilic acid (1.0 g.), 4 Nhydrochloric acid (15 ml.), and ethanol (15 ml.) is refluxed for 5hours. The solvents are removed in vacuo. The residue is treated withwater (15 ml.) and an excess of solid sodium acetate. The resultingprecipitate is filtered ofl? and washed with water. After drying andrecrystallizing from ethanol, 4-phenylthio-5-sulfamyl-anthranilic acidis obtained with a melting point of 263-264 C. (dec.).

EXAMPLE 49 4-phenylsulfinyl-5-sulfamyl-N-benzyl-anthranilic acid To asolution of 4-phenylthio-S-sulfamyl-N-benzylanthranilic acid (1.5 g.) inacetone ml.) is added 30 percent H 0 (0.6 ml.), and the mixture isstirred at room temperature for 20 hours. The solvent is removed invacuo, and the resulting crystalline material is triturated with diethylether, filtered off, and washed with diethyl ether. After drying,4phenylsulfinyl-S-sulfamyl-N-benzylanthranilic acid is obtained.

EXAMPLE 50 4-phenylsulfonyl-5-sulfamyl-N-benzyl-anthranilic acid Amixture of 4-phenylthio-5-sulfamyl-N-benzyl-anthranlhc acid (0.5 g.), 30percent H 0 (2.5 ml.), and acetic acid (5 ml.) is stirred at roomtemperature for 20 hours. The mixture is diluted with water (10 ml.),and the precipitate is filtered ofi? and washed with water. After dryingand recrystallizing from methyl-Cellosolve,4-phenylsulfonyl-5-sulfamyl-N-benzyl-anthranilic acid is obtained with amelting point of 290-291 C. (dec.).

EXAMPLE 51 4-phenoxy-5-phenylsulfamyl-N-benzyl-anthranilic acid (a) 2-chloro 4 fiuoro 5 phenylsulfamyl benzoic ac d.-A mixture of2-chloro-4-fiuoro-5-chlorosulfonylacid (5 g.), aniline (5 ml.), sodiumhydrogen carbonate (5 g.), and 50 percent ethanol (25 ml.) is stirred atroom temperature for 20 hours. The solvents are removed in vacuo, andthe residue is diluted with water (50 ml.) and extracted twice withdiethyl ether. The aqueous solution 1s acidified with concentratedhydrochloric acid (5 ml.).

15 The resulting precipitate is filtered ofl? and washed with water.After drying and recrystallizing from 50 percent ethanol,2-chloro-4-fiuoro-S-phenylsulfamyl-benzoic acid is obtained with amelting point of 204.5-20S5 C.

(b) 2 chloro 4 phenoxy S-phenylsulfamyl-benzoic acid.A mixture of2-chloro-4fluoro-5-phenylsulfamylbenzoic acid (4 g.), phenol (16 g.),and potassium hydroxide (3.5 g.) is heated While stirring to 150-160" C.for 3 hours. The mixture is diluted with water (25 ml.) and extractedtwice with diethyl ether. The aqueous solu tion is acidified withconcentrated hydrochloric acid (5 ml.), and the resulting precipitate isfiltered off and washed with Water and with cold 50 percent ethanol.After drying and recrystallizing from aqueous ethanol, 2-chloro-4-phenoxy-5-phenylsulfamyl-benzoic acid is obtained with amelting point of 23 3-234" C.

(c) 4 phenoxy-S-phenylsulfarnyl-N-benzyl-anthranilic acid.A solution of2-chloro-4-phenoxy-5-phenylsu1- famyl-benzoic acid (2 g.) andbenzylamine (6 ml.) in methyl-Cellosolve (6 ml.) is refluxed for 1 6hours. The mixture is poured into 4 N-acetic acid (25 ml.). Theresulting precipitate is filtered off and washed with water. Afterdrying and recrystallizing from ethanol, 4-phenoxy-5-phenylsulfamyl-N-benzyl-anthranilic acid is obtained with a meltingpoint of 235.5-236 C.

EXAMPLE 52 4-phenylthio-5-4-methoxyphenylsulfamyl -N-benzylanthranilicacid (a) 2-chloro-4-fluoro-5-(4-methoxyphenylsulfamyl) benzoic acid.Amixture of 2-chloro-4-fluoro-5-chlorosulfonyl-benzoic acid (5 g.),p-anisidine (S g.), sodium hydrogen carbonate (5 g.), and 50 percentethanol (25 ml.) is stirred at room temperature for 20 hours. Thesolvents are removed in vacuo. The residue is diluted with water (50ml.) and extracted twice with diethyl ether. The aqueous solution isacidified with concentrated hydrochloric caid (5 ml.). The resultingprecipitate is filtered ofi and washed with water. After drying andrecrystallizing from aqueous ethanol,2-chloro-4-fluoro-5-(4'-methoxyphenylsulfamyl)-benzoic acid is obtainedwith a melting point of 190l91 C.

(b) 2-chloro-4-phenylthio-5-(4-methoxyphenylsulfarnyl)-benzoic acid.Asolution of 2-chloro-4-fluoro-S-(4'- methoxyphenyl-sulfamyl)-benzoicacid (4.75 g.), thio phenol (2 ml.), and sodium hydrogen carbonate (10g.) in water (25 ml.) is heated on a steam bath for 4 hours. Aftercooling, the solution is acidified with concentrated hydrochloric acid.The resulting precipitate is filtered off and washed with water and aminor amount of cold 50 percent ethanol. After drying andrecrystallizing from ethanol, 2-chloro-4-phenylthio-5-(4'-methoxyphenyl)-benzoic acid is obtained with a melting point of 218219 C.

(c) 4-phenylthio 5 (4-methoxyphenylsulfamyl)-N- benzyl-anthranilicacid.A mixture of2-chloro-4-phenylthio-S-(4'-methoxyphenylsulfamyl)-benzoic acid (1 g.)and benzylamine (4 ml.) is heated to 140 C. for 4 hours. The mixture ispoured into 4 N acetic acid (25 ml.). The resulting precipitate isfiltered 011 and washed with water. After drying and recrystallizingfrom aqueous ethanol, 4-phenylthio 5(4'-methoxyphenylsulfamyl)-N-benzylanthranilic acid is obtained with amelting point of 200- 201 C. (dec.).

EXAMPLE 53 4-phenoxy-5- (N-acetylsulfamyl) -N-benzyl-anthranilic acid Toa suspension of 4-phenoxy-S-sulfamyl-N-benzylanthranilic acid (1.0 ml.)in water (25 ml.), 2 N lithium hydroxide is added through an automaticendpoint titrator until pH=11.0. To the resulting solution, acetic acidanhydride (1.0 ml.) is added in portions, keeping the pH at 11.0 by theaddition of 2 N lithium hydroxide through the titrator. When the baseconsumption ceases, the solution is acidified with concentratedhydrochloric acid (2.0 ml.). The resulting precipitate is collected byfiltration 16 and washed with water. After drying and recrystallizingtwice from a mixture of ethanol and methyl-Cellosolve, 4 phenoxy 5(N-acetyl-sulfamyl)-N-benzyl-anthranilic acid is obtained with a meltingpoint of 250-250.5 C. (dec.).

EXAMPLE 54 4-phenoxy-5-N- N-n-bzutylcarbamyl -sulfarnyl] -N- benzylanthranilic acid To a solution of4-phenoxy-5-sulfamyl-N-benzyl-anthranilic acid (1.33 g.) in a mixture of1 N lithium hydroxide (6.7 ml.) and acetone (6.7 ml.), a solution ofnbutylisocyanate (0.38 ml.) in acetone (0.4 ml.) is added dropwise whilestirring at 10 C. The resulting solution is stirred at room temperaturefor a further 24 hours. Water (10 ml.) is added, and the mixture isextracted with diethyl ether. The aqueous phase is separated andacidified with 4 N hydrochloric acid (2 ml.). The resulting precipitateis collected by filtration and washed with Water. After drying andrecrystallizing twice from ethyl acetate, 4 phenoxy 5[N-(N'-n-butylcarbamyl)-sulfamyl]-N- benzyl-anthranilic acid is obtainedwith a melting point of 217-219 C. (dec.).

EXAMPLE 55 Methyl 4-phenoxy- S-sulfamyl-N- [furyl- (2) -methyl]-anthranilate (a) Methyl 2-chloro-4-phenoxy-5-sulfamylbenzoate. Asolution of Z-chloro-4-phenoxy-S-sulfamyl-benzoic acid (10 g.) inmethanol (200 ml.) is saturated with hydrogen chloride and leftovernight. The solution is evaporated in vacuo, and the crystallineresidue is washed with saturated in vacuo, and the crystalline residueis washed with saturated sodium hydrogen carbonate solution (25 ml.) andcollected by filtration. After drying and recrystallizing from aqueousmethanol, methyl 2-chloro-4-phenoxy-5- sulfamyl-benzoate semihydrate isobtained with a melting noint of 93-95 C.

(b) Methyl 4 phenoxy-S-sulfamyl-N-[furyl-(2)-methyl]-anthranilate.Asolution of methyl 2-chloro-4-phenoxy-5-sulfamyl-benzoate (2.0 g.) infurfurylamine (8.0 ml.) is stirred at C. for 3.5 hours. The mixture ispoured into cold 4 N- acetic acid (40 ml.). The initially precipitatedoil crystallizes on standing overnight. The crystalline material iscollected by filtration and washed with water. After drying andrecrystallizing twice from methanol and from ethylacetate, methyl4-phenoxy-5- sulfamyl-N-[furyl-(2)-methyl]-a.nthranilate is obtainedwith a melting point of 137.5-139" C.

EXAMPLE 5 6 Methyl 4-phenylthio-5-sulfarnyl-N- [furyl 2) -methyl]anthranilate i(a) Methyl 2 chloro-4-phenylthio-5-sulfamyl-benzoate.--Byreplacing, in Example 55a, the 2-chloro-4-phenoxy-S-sulfamyl benzoicacid by 2-chloro-4-phenylthio-5- sulfamylbenzoic acid, methyl2-chloro-4-phenylthio-5-sulfamyl-benzoate is obtained with a meltingpoint of 159- 160.5 C.

(b) Methyl 4 phenylthio 5 sulfamyl-N- [furyl-(2)- methyl]-anthranilate.--By replacing, in Example 55b, the methyl2-chloro-4-phenoxy5-sulfamyl-benzoate by methyl 2 chloro 4phenylthio-S-sulfamyl-benzoate, methyl 4- phenylthio 5 sulfamyl-N-[furyl-(2)-methyl]-anthranilate is obtained with a melting point of187-189 C.

EXAMPLE 57 Cyanomethyl 4-phenoxy-S-sulfamyl-N-benzyl-anthranilate Asolution of 4-phenoxy-S-sulfamyl-N-benzyl-anthranilic acid (3.6 g.),chloroacetonitrile (1.0 g.), and triethylarnine (0.99 g.) in dry acetone(30 ml.) is refluxed for .20 hours and then evaporated in vacuo. Theresidue is triturated with 1 N sodium hydrogen carbonate solution (20ml.), and the undissolved material is extracted with ethyl acetate(about 50 ml.). The organic layer is washed with water, dried (MgSO andevaporated in vacuo. The residue is triturated with cold 50 percentisopropanol (20 ml.). The resulting crystalline material is collected byfiltration and washed with cold 50 percent isopropanol. After drying andrecrystallizing from 50 percent isopropanol, cyanomethyl4-phenoXy-5-su1famyl N benzyl-anthranilate is obtained with a meltingpoint of l32l34 C.

What we claim is:

1. Compounds of the formula R HN02 C O OH and pharmaceuticallyacceptable salts thereof; and esters thereof with cyanomethanol, benzylalcohol, or lower alkanols; wherein:

R R R and R are alkyl with not more than 7 carbon atoms, said alkylbeing optionally substituted with hydroxy, lower alkoXy, di-loweralkylarnino or phenyl, provided that when substituted with phenyl, saidalkyl contains from 1 to 4 carbon atoms, the phenyl moiety beingoptionally substituted with chlorine, bromine, methoxy, dimethoxy ormethyl; alkenyl with not more than 3 carbon atoms, propargyl,naphthylmethyl, cycloalkyl having no more than 8 carbon atoms,cyclopentenyl, cyclohexenyl or adamantyl;

provided that R R and R may also be hydrogen; R may also be acetyl,phenyl, methoxyphenyl; R may also be phenyl, halophenyl,trifiuoromethylphenyl, methylphenyl, methoxyphenyl, acetylamino phenylor naphthyl; further provided that when one or both of R and R arehydrogen or an aliphatic radical A is different from an aliphatic Rgroup. 2. 4-phenoXy-5-sulfamyl-N-benzyl-anthranilic acid. 3.4-phenoxy-5-sulfamyl-N-n-buty1-anthranilic acid. 4.4-(4-chlorophenoxy)-5-sulfamyl-N-benzyl anthranilic acid.

5. 4-(3'-methylphenoxy)-5-sulfamyl N benzyl-anthranilic acid.

6d. 4 phenylsulfonyl sulfamyl-N-benzyl-anthranilic acl 1 8 7. Compoundsof the formula R HNOgS C 0 0H and pharmaceutically acceptable saltsthereof; and esters thereof with cyanomethanol, benzyl alcohol, or loweralkanols; wherein:

R and R are hydrogen, alkyl with not more than 5 carbon atoms, alkenylwith not more than 3 carbon atoms, hydroxyalkyl with not more than 3carbon atoms, alkoxyalkyl with not more than 4 carbon atoms,dialkylaminoalkyl with not more than 5 carbon atoms, phenylalkyl, thephenyl moiety being optionally substituted with chlorine, methoxy,methyl, or dimethoxy, and the alkyl moiety contains from 1 to 3 carbonatoms, or naphthylmethyl;

R is hydrogen, methyl, phenyl, methoxyphenyl, or acetyl;

R is alkyl having 2 to 4 carbon atoms being optionally substituted withmethoXy or phenyl, phenyl, halophenyl, trifiuoromethylphenyl,methylphenyl, methoxyphenyl, acetylaminophenyl, or naphthyl;

provided that when one or both of R and R are hydrogen or an aliphaticradical, A is different from an aliphatic R O-group.

References Cited UNITED STATES PATENTS 3,444,177 5/1969 Schmidt et al260-518 R OTHER REFERENCES Fieser, L. F., Organic Chemistry (1956), 3rdedition, pub. by Reinhold Pub. Corp.-New York, p. 627 relied on.

LORRAINE A. WEINBERGER, Primary Examiner L. A. THAXTON, AssistantExaminer US. Cl. X.R.

